The overall objective of this proposal is to determine the existence and physiological significance of interdependence of ventilatory stimuli between central chemoreceptive/integrative centers and other peripheral and central ventilatory-related afferent inputs. Such interdependence is predicted by a recent model of ventilatory control based on newer neuroanatomical knowledge of the ventilatory control system. Our approach will be to quantify the interaction (hyperadditive, hypoadditive, or additive - i.e. no interaction) of the central chemoreceptors with key afferent inputs predicted to modulate the putative central chemosensors/integrator. Specifically, we will test the effect on the gain of the central chemoreceptors of: a) acute stimulation and inhibition of carotid body (CB) chemoreceptors during wakefulness and sleep; b) chronic hypoxic stimulation of carotid body (CB) chemoreceptors during wakefulness (acclimatization); c) normal physiological exercise with CB chemoreceptors held normocapnic and normoxic. To achieve this we will use our unique unanesthetized animal preparation, which allows separation of the environments of the central and peripheral chemoreceptors by means of reversible isolation and perfusion of the CB chemoreceptors. Using this preparation we can stimulate, inhibit, or maintain normal the carotid body chemoreceptors independently from the central chemoreceptors. We predict that we will observe hyperadditive interaction of the central chemoreceptors with all key afferent inputs thus confirming an interdependence between them. If confirmed, this concept will have a significant impact on our current understanding of the control of breathing in both health and disease. Our findings could be of particular importance in understanding: a) if the normal drive to spontaneous eupnea at rest in a normoxic environment depends critically on a gain-setting effect on the central chemoreceptor/integrator by the level of tonic sensory input from the CB chemoreceptors; b) the genesis of sleep apnea; c) the periodic breathing of heart failure; d) any pathological or environmental situation where chronic hypoxia is present; e) whether increased central chemosensitivity contributes significantly to exercise hyperpnea in health and especially in the presence of heart failure or chronic hypoxia, i.e., under conditions where CB chemoreceptor sensitivity is known to be upregulated. PUBLIC HEALTH RELEVANCE: This study is relevant to public health because it will attempt to explain some of the fundamental mechanisms underlying the control of breathing in health and disease. It is hoped that better understanding of these mechanisms will lead to better solutions for prevention and/or treatment of breathing disorders, particularly that of sleep apnea, as well as exercise intolerance in cardiovascular diseases such as congestive heart failure.